The present invention is concerned with the amino-methylation of the unsubstituted positions on the benzene ring of tocopherols, especially the complete aminomethylation of xcex3-tocopherol either alone or as a component of a mixture of several so-called xe2x80x9cnon-xcex1-tocopherolsxe2x80x9d containing this tocopherol as well as, e.g., xcex2- and xcex3-tocopherol.
It is known from the relevant literature that the conversion of xcex3-tocopherol, which differs from xcex1-tocopherol by the presence of two unsubstituted positions (5- and 7-) on the benzene ring, into the corresponding 5,7-bis(aminomethyl) derivatives takes place only incompletely. An incomplete aminomethylation of xcex4-tocopherol leads, after the catalytic reduction performed subsequently in order to convert the aminomethylated product to (xcex1-tocopherol, to an xcex1/xcex2-tocopherol mixture which can only then be converted into xcex1-tocopherol by an additional reaction cycle of aminomethylation+catalytic reduction. As an alternative to this additional cycle, the initially-produced xcex1-tocopherol can be separated from the mixture of xcex1/xcex2-tocopherols, which of course likewise leads to an unsatisfactorily low yield of xcex1-tocopherol, which tocopherol is preferred for known biological reasons over the non-xcex1-tocopherols. For these reasons, the previously known processes for the aminomethylation of xcex4-tocopherol have been found to be expensive and accordingly uneconomical, which also applies to the aminomethylation of tocopherol mixtures containing xcex4-tocopherol.
Thus, Nakamura and Kijima [Chem. Pharm. Bull. 19(11), 35 2318-2324 (1971)] have reacted xcex4-tocopherol with in each case eight mol equivalents of aqueous dimethylamine solution and 37% formalin at reflux temperature for 4 hours and in this way obtained (see pages 2320 and 2322) a mixture of the 5-mono-substituted product, 5-dimethylaminomethyl-xcex4-tocopherol (57% yield), and the 5,7-disubstituted product, 5,7-bis(dimethylamino-methyl)-xcex4-tocopherol (only 31% yield). This result is obviously due to the fact that the 5-position of the xcex4-tocopherol molecule is substantially more reactive to aminomethylation than the 7-position and that the substitutability of the still free 7-position is further impeded by the introduction of the first amino substituent. The problem of incomplete aminomethylation is also evident in European Patent Publication (EP) 159 018 of the Henkel Corp., where the aminomethylation of a tocopherol mixture and the subsequent separation of the aminomethylated xcex2-, xcex4- and xcex3-tocopherols from the unreacted xcex1-tocopherol are disclosed. After catalytic hydrogenation of the aminomethylated tocopherols, the thus-obtained mixture of xcex1-, xcex2-, xcex4- and xcex3-tocopherols is again aminomethylated and hydrogenated in order to obtain (see pages 16-19) a product having a high as possible content of xcex1-tocopherol. This second round of aminomethylation and hydrogenation comprises the aforementioned xe2x80x9cadditional reaction cyclexe2x80x9d which the incomplete aminomethylation of the prior art required.
The object of the present invention is to carry out the aminomethylation of xcex4-tocopherol or of tocopherol mixtures containing xcex4-tocopherol as completely and accordingly as economically as possible. This object is achieved by performing the aminomethylation reaction using a Mannich reagent (reaction product of formaldehyde or a formaldehyde-producing compound and a secondary amine) which has been produced by reacting formaldehyde or a formaldehyde-producing compound, preferably paraformaldehyde as the formaldehyde-producing compound, with a secondary amine in the complete or almost complete absence of a solvent. Accordingly, the present invention is concerned with the aminomethylation process carried out in this manner, the process for the production of the Mannich reagent itself, as well as the Mannich reagent produced in this manner.
The process in accordance with the invention for the aminomethylation of the unsubstituted positions of the benzene ring of xcex4-tocopherol or of tocopherol mixtures containing xcex4-tocopherol comprises reacting the xcex4-tocopherol or tocopherol mixture with a Mannich reagent which has been produced by reacting formaldehyde or a formaldehyde-producing compound with a secondary amine in the complete or almost complete absence of a solvent. The separate (carried out prior to the actual aminomethylation) production of the Mannich reagent, as well as the thus-produced Mannich reagent itself are further aspects of the present invention.
A Mannich reagent is the product of a reaction between formaldehyde and a secondary amine. The reaction ultimately forms an iminium ion which is the reactive species. However, the iminium ion exists in equilibrium with the reactants and an intermediate hydroxymethyl-secondary amine, as follows: 
wherein R1 and R2 are as defined herein below.
In accordance with the invention, formaldehyde or a formaldehyde-producing compound may be reacted with the secondary amine to produce the Mannich reagent. For the purposes of this invention, a formaldehyde-producing compound is any compound which acts as a source of formaldehyde to react with the secondary amine to form the Mannich reagent. The preferred formaldehyde-producing compound is paraformaldehyde. For simplicity, reference to formaldehyde herein also includes formaldehyde-producing compounds.
For the production of the Mannich reagent, the formaldehyde is added to the secondary amine portionwise and sufficiently slowly such that the temperature of the reaction mixture does not rise too rapidly (the reaction is exothermic). Moreover, the mixture is preferably stirred during and after completion of the addition. Preferably, between 0.7 and 1.2 mole equivalents of formaldehyde, more preferably between 0.9 and 1.1 mole equivalents, are used per mole equivalent of the secondary amine.
The temperature at which the Mannich reagent is prepared is not critical. Any temperature at which formaldehyde will react with a given secondary amine may be used in accordance with the invention. Sincexe2x80x94as mentioned abovexe2x80x94the reaction is exothermic, it is usually not necessary to heat the reaction mixture above the required initial reaction temperature which, depending on the secondary amine used, normally lies in the range of about 500xc2x0 C. to about 700xc2x0 C. Having regard to the exothermic nature of the reaction, the temperature tends to increase in the course of the reaction by a few degrees, normally by up to about 20 degrees Celsius, i.e. up to about 70xc2x0 C.-90xc2x0 C.
Therefore, one aspect of the invention comprises a process for the production of a Mannich reagent, which process comprises reacting formaldehyde in the absence of an inert solvent with a secondary amine of the formula: 
wherein R1 and R2 are the same or different and are C1-6-alkyl, C2-6-hydroxyalkyl or C2-6-alkoxyalkyl, or taken together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclic ring, which is unsubstituted or substituted by C1-6-alkyl, and which heterocyclic ring contains at most one additional heteroatom selected from the group consisting of oxygen and nitrogen,
wherein the ratio of said formaldehyde to said secondary amine in said reaction in mole equivalents is in the range from 0.7:1 to 1.2:1, so that said formaldehyde and said secondary amine are reacted to produce said Mannich reagent.
Preferably, 0.9 to 1.1 mol equivalents of formaldehyde are reacted with 1 mol equivalent of secondary amine. As noted above, the form of formaldehyde used is preferably paraformaldehyde.
In principle, any secondary amine which conventionally comes into consideration for aminomethylation can be used for the production of the Mannich reagent. For practical reasons, there is, however, preferably used a di(C1-6-alkyl)amine, a di(C2-6-hydroxyalkyl)amine, a di(C2-6-alkoxyalkyl)amine or a cyclic amine formed when R1 and R2, above, are taken together with the nitrogen atom to which they are attached. The cyclic amine is a 5-to 8-membered ring compound which contains at most one further heteroatom, either oxygen or nitrogen. The ring can be substituted on the its carbon atoms as well as on the further nitrogen atom optionally present. In the case of a substituted cyclic amine the preferred substitutents are lower alkyl groups (C1-6-alkyl groups).
When not taken together with the nitrogen to which they are attached to form a heterocyclic ring, R1 and R2 are preferably independently methyl, ethyl, hydroxyethyl or methoxyethyl. More preferably R1 and R2 are the same. Therefore, examples of dialkylamines are dimethylamine and diethylamine; an example of a di(hydroxyalkyl)amine is di(hydroxyethyl)amine; and an example of a di(alkoxyalkyl)amine is di(methoxyethyl)amine.
When taken together with the nitrogen atom to which they are attached to form a heterocyclic ring, rings of 5 or 6 members are preferred. Examples of such cyclic amines are, pyrrolidine, piperidine, 1-methyl-piperazine and morpholine, of which 1-methyl-piperazine and morpholine are preferred.
The course of the reaction between the formaldehyde and the secondary amine can be followed in a conventional manner, e.g., by NMR analysis of a sample of the reaction mixture. Thereby, it is established that this mixture during the reaction has an ever-increasing content of the respective diaminomethane, e.g., dimorpholinomethane when formaldehyde is reacted with morpholine as the secondary amine. Of course, other components are always present, inter alia the corresponding N-hydroxy-methylamine, e.g., morpholinomethanol. Normally, the exothermic reaction has finished within about 1 to 2 hours. The thus-produced Mannich reagent can be stored for several weeks at room temperature.
It is surprising and an advantage of the process in accordance with the invention that the use of a solvent can be dispensed with in the production of the Mannich reagent.
The aminomethylation procedure using the Mannich reagent is carried out by adding the Mannich reagent produced as described above to the xcex4-tocopherol or to a tocopherol mixture containing xcex4-tocopherol, or by performing the reverse addition, and heating the reaction mixture resulting therefrom while stirring in the temperature range between about 1000xc2x0 C. and about 1400xc2x0 C.
Preferably, about 2.5 to 10 mole equivalents of Mannich reagent (based on the amount of secondary amine or formaldehyde used for its production, depending on which amount is smaller and accordingly determinative) are used per mole equivalent of xcex4-tocopherol or total present non-xcex1-tocopherols (xcex4-tocopherol as well as xcex2-tocopherol and/or xcex3-tocopherol). The pressure under which the reaction is carried out is not critical. The reaction can be carried out under normal pressure or under elevated pressure, for example in the latter case by carrying out the reaction in a sealed autoclave.
Thus, a further aspect of the invention is a process for the bis-aminomethylation of the unsubstituted positions on the benzene ring of xcex4-tocopherol, which process comprises forming a reaction mixture of a Mannich reagent and said xcex4-tocopherol wherein the mole ratio of said Mannich reagent to said xcex4-tocopherol in said reaction mixture is in a range from 2.5:1 to 10:1, said Mannich reagent being obtained by a process which comprises reacting formaldehyde or a formaldehyde-producing compound in the absence of an inert solvent with a secondary amine of the formula: 
wherein R1 and R2 are as described above,
wherein the ratio of said formaldehyde or formaldehyde-producing compound to said secondary amine in said reaction in mole equivalents is in the range from 0.7:1 to 1.2:1, to obtain said Mannich reagent,
by which process the benzene ring of said xcex4-tocopherol is bis-aminomethylated.
Since it is known that vegetable oils and fats such as, for example, soya oil, rape oil, cotton seed oil, peanut oil, wheatgerm oil, corn oil, barley oil, rye oil, thistle oil and the like are valuable natural sources of tocopherols (inter alia xcex1- and xcex4-tocopherol), such oils or their distillates, which have a high content of tocopherols and little undesired extraneous components, e.g., sterols, free and esterified fatty acids, waxes and glycerides, can be used as the starting material in the aminomethylation process in accordance with the invention. In particular, thistle oil and soya oil have been found to be valuable sources of tocopherols, inter alia xcex1-tocopherol and the xcex4-tocopherol converted in accordance with the invention into this. It is, of course, unimportant that, inter alia, xcex1-tocopherol itself is present in the educt, since the xcex1-tocopherol does not prevent the conversion of xcex4-tocopherol into xcex1-tocopherol and itself remains in unreacted form in the product of the process.
The course of the aminomethylation is conveniently followed by gas-chromatographic (GC) analysis of the reaction mixture, advantageously by GC analysis of silylated samples. In this way, the decreasing content of the respective 5-aminomethyl-xcex4-tocopherol and the correspondingly increasing content of the respective 5,7-bis(aminomethyl)-xcex4-tocopherol are established. Normally, the aminomethylation has finished within about 3 to 8 hours. The excess Mannich reagent may be recovered by distillation.
A further advantage of the aminomethylation process in accordance with the invention is that the distillatively separated excess Mannich reagent can, after regeneration, be used for further aminomethylations. The reuse of the Mannich reagent can be repeated several times with good results. The regeneration itself is conveniently carried out by adding water to the distillatively-separated excess Mannich reagent at room temperature and, while stirring, heating the resulting aqueous mixture to about 80xc2x0 C. and subsequently adding further formaldehyde, preferably in the form of paraformaldehyde, while stirring. Then, the mixture is preferably further stirred at this temperature for about an additional 3 hours. About equimolar amounts of the three reactants are suitably used in this regeneration, with the deviation preferably not being more than about 10%.
Therefore, a further aspect of the invention is a process for the regeneration of a Mannich reagent remaining after a bis-aminomethylation reaction where said remaining Mannich reagent had been obtained by a process which comprised reacting formaldehyde or a formaldehyde-producing compound in the absence of an inert solvent with a secondary amine of the formula: 
wherein R1 and R2 are as described above, wherein the ratio of said formaldehyde or formaldehyde-producing compound to said secondary amine in said reaction in mole equivalents was in the range from 0.7:1 to 1.2:1, to obtain said Mannich reagent, said regeneration comprising: separating said Mannich reagent from said bis-aminomethylation reaction, and reacting said separated Mannich reagent with about equimolar amounts of water and formaldehyde or a formaldehyde-forming compound to regenerate said Mannich reagent.
The regeneration reaction may be carried out at any temperature sufficient to regenerate said Mannich reagent. Preferably, the temperature is in the range from 70xc2x0 C. to 90xc2x0 C., especially about 80xc2x0 C.
As an alternative to the use of the Mannich reagent which has been prepared essentially solvent-free, there can be used in the aminomethylation process of the invention a Mannich reagent which has been prepared from the respective diaminomethane (prepared from a secondary amine), e.g., dimorpholinomethane, and formaldehyde (preferably as paraformaldehyde) as well as water in about equimolar amounts. Preferably, these equimolar amounts do not deviate by more than about 10%. The three reactants are heated to about 70-900xc2x0 C. and reacted with one another at this temperature for usually not more than about three hours, preferably about 1 to 1xc2xd hours.
Thus, a further aspect of the invention is a process for the production of a Mannich reagent, which process comprises reacting about equimolar amounts of a compound of the formula: 
wherein R1 and R2 are as described above, with formaldehyde or a formaldehyde-producing compound, and water, to produce said Mannich reagent.
In contrast to the production of the Mannich reagent from the secondary amine and formaldehyde, the present reaction is not especially exothermic. The product hardly differs in its composition and activity from the Mannich reagent of the essentially solvent-free process and from regenerated Mannich reagent. The production of the Mannich reagent in this manner can even be carried out in the presence of the xcex4-tocopherol or of a tocopherol mixture containing this tocopherol, so that the aminomethylation itself immediately follows the production of the Mannich reagent.
The production and use of the two xe2x80x9calternativexe2x80x9d Mannich reagents form further aspects of the present invention.
The aforementioned diaminomethanes are either known or can be produced according to methods known per se, especially starting from the corresponding secondary amines.
In order finally to proceed to the desired xcex1-tocopherol, the product of the aminomethylation in accordance with the invention, which contains a high amount of diaminomethylated xcex4-tocopherol and, depending on the tocopherol mixture (educt) used, monoaminomethylated xcex2- and/or xcex3-tocopherol, as well as unchanged, originally-present xcex1-tocopherol, can be reduced, e.g. catalytically hydrogenated to the desired xcex1-tocopherol. This hydrogenation can be effected by any conventional means [see, for example, EP 159 018, U.S. Pat. No. 2,486,539 as well as U.S. Pat. No. 2,519,863].
The hydrogenation is preferably carried out using a palladium catalyst in a non-polar solvent, e.g., a dialkyl ether, especially tert.butyl methyl ether, or a hydrocarbon, e.g., n-hexane or cyclohexane. The hydrogenation requires according to experience reaction temperatures of about 1500xc2x0 C. to about 210xc2x0 C. a hydrogen pressure of about 15 to about 50 bar as well as a reaction time of about 2 to about 10 hours. The isolation and purification of the desired xcex1-tocopherol following hydrogenation can also be effected according to methods known per se.
The present invention embraces as a further aspect the novel bis(aminomethyl)-xcex4-tocopherols, i.e. the novel disubstituted [bis(aminomethylated)] xcex4-tocopherols manufacturable in accordance with the invention from the respective Mannich reagents and xcex4-tocopherol, namely of the formula: 
wherein R1 and R2 are the same or different and are C2-6-alkyl, C2-6-hydroxyalkyl or C2-6-alkoxyalkyl, or taken together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclic ring, which is unsubstituted or substituted by C1-6-alkyl, and which heterocyclic ring contains at most one additional heteroatom selected from the group consisting of oxygen and nitrogen.
In the case of the substituted cyclic amino group there come into consideration as substitutents especially lower alkyl groups (primarily C1-6-alkyl groups). When not taken together with the nitrogen to which they are attached to form a heterocyclic ring, R1xe2x80x2 and R2xe2x80x2 are preferably independently ethyl, hydroxyethyl or methoxyethyl. More preferably R1 and R2xe2x80x2 are the same. When taken together with the nitrogen atom to which they are attached to form a heterocyclic ring, rings of 5 or 6 members are preferred. Preferred heterocyclic groups R1xe2x80x2R2xe2x80x2N are pyrrolidino, piperidino, N-methylpiperazino and morpholino.
Formula I, in which the abbreviated form of representation usual in tocopherol chemistry (using simple lines) is used, embraces isomeric forms, especially optically active isomers, as well as mixtures thereof unless expressly mentioned to the contrary. As examples of chiral (optically active) centres there are to be mentioned the carbon atom carrying the methyl group and the 4,8,12-trimethyltridecyl group (denoted as 2 in formula I) as well as the 4- and 8-carbon atoms of the said trimethyltridecyl group (denoted as 4xe2x80x2 and 8xe2x80x2, respectively).
Six aforementioned specific novel compounds of formula I as well as three other novel compounds of formula I were obtained after chromatography on silica gel as colourless or light yellowish, viscous oils starting from natural d-tocopherol in each case having the 2R,4xe2x80x2R,8xe2x80x2R configuration. The 1H-NMR spectra obtained for these disubstituted xcex4-tocopherols had no signals between 5 and 9 ppm, which demonstrates the complete substitution of the benzene nucleus. The physical data of the nine compounds are given in the following Table in which xe2x80x9cc%xe2x80x9d signifies concentration in weight percent:
5,7-Bis(morpholinomethyl)-xcex4-tocopherol and 5,7-bis(N-methylpiperazinomethyl)-6-tocopherol are especially preferred bis(aminomethyl)-xcex4-tocopherols of formula I.
A further advantage is present in the aminomethylation process which is used for the production of the disubstituted xcex4-tocopherols: where the educt (xcex4-tocopherol) is a pure isomer, e.g., is in the 2R,4xe2x80x2R,8xe2x80x2R configuration, the stereochemical purity is retained in the 5,7-disubstituted (aminomethylated) product.